Cheryl A. Abbas, PharmD

Clinical Pharmacist

Advanced Heart Failure and Heart Transplant

Thomas Jefferson University Hospital

Complications of Continuous-Flow Left

Ventricular Assist Devices

Review the physiological effects of a continuous-flow left-ventricular assist device (CF-LVAD)

Understand the role of pharmacotherapy in the management of CF-LVADs

Evaluate clinical symptoms and device findings in the diagnosis of CF-LVAD complications

Describe the pharmacotherapy of device-related complications

Objectives

Progression of heart failure leads to refractory treatments~250,000 of 7 million patients will develop advanced

diseaseInotropic support survival rate of 10-30% at 1 year

Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)Fifth annual report: 7,000 patients in the United States

Increase in implanting centers from ~109 to ~147 in January 2011 to 2012

Role of Mechanical Circulatory Support

Chetan PB. J Heart Lung Transplant 2014;33:667-674.

Implanted pump delivering blood from left ventricle to ascending aortaFlow rate up to 10 liters per minuteMean pressure of 100 mm HG

Continuous flow vs. pulsatile devicesGreater durability Reduced size and weightSilent operationImproved quality of life

Left Ventricular Assist Devices (LVADs)

Continuous-flow Devices

BTT = Bridge to TransplantDT = Destination Therapy

Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.

Patient assessment:Appropriateness based on degree of illness

Heart Failure Survival Score; Seattle Heart Failure ScoreAbility to undergo operative procedureAdequate family/caregiver support for long-term

success

LVAD Candidacy

Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.

HeartMate II (HMII)

Rotary blood pump

Percutaneous driveline to external controller

External batteries or power-based unit

Estimated lifespan of pump: 5-10 years

CF-LVAD Physiology

Slaughter, MS. N Engl J Med 2009;361:2241-51.

Speed: Fixed in range of 8,000 – 12,000 RPMs

Power: Direct measure of voltage to motor (4-7 watts)

Flow: Estimated speed x power (3-7 liters/minute)Afterload sensitive - affected by hypertension

↑AO → ↓ Flow↓AO → ↑ Flow

Pulsatility Index (PI): Flow pulse through pump (4-8)Native LV contractility and volume status

CF-LVAD Parameters

Thoratec Press Kit: HMII Pivitol Trial Fact Sheet.

Pharmacotherapy in CF-LVAD

Blood Pressure MonitoringHemodynamic effect of CF-LVAD: Increase in

diastolic pressure and flowReduced pulse pressure

Difficult to palpate pulseMean arterial blood pressure (MAP) measured by

doppler

Goal MAP: 70-80 mmHGAmount of cardiac output by CF-LVAD affected

by afterloadMaintaining goal = optimized cardiac output

Reduces stroke due to hypertension

Blood Pressure ManagementVasoactive agents

ACEi/ARB, β-blockade, hydralazine, nitrates

Hypertension: assess BP and volume status CF-LVAD parameters

Decrease in pump flow and powerIncrease in PI

Management: Decrease afterload with medicationsConsider diuretics for volume overload

Hypotension: symptoms, BP monitoring CF-LVAD parameters

Increase in pump flow and powerDecrease in PI

Management: Adjust vasoactive agentsIntravascular fluid volume management

Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.

Required to avoid thrombotic complications

Early BTT HeartMate II trials included aggressive anticoagulation (AC)Target INR range 2.5 to 3.5 Incidence of thrombosis < bleeding resulted in reduced AC

therapy

ISHLT MCS GuidelinesAnticoagulation: Warfarin with target INR based upon

manufacturerHeartMate II: 2.0 to 3.0

Antiplatelet: Aspirin 81-325 mg daily in addition to warfarinAdditional agents may be added

Anticoagulation

Feldman, D. J Heart Lung Transplant 2013;32:157-187.

Boyle, et al evaluated long term AC therapy in 331 HeartMate II outpatientsRisk of thrombosis increased with INR < 1.5

Risk of hemorrhagic events present at all INR ranges; increased with INRs > 2.5

Anticoagulation

Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.

Increased platelet activation from sheer stress

Agents:Aspirin 81-325 mg dailyClopidogrel 7g mg dailyDipyridamole 75 mg tidPentoxifylline 400 mg tid

Lack of data: Ticagrelor and Prasugrel

Hypo- or non-responsiveness is commonly seenDoubling of dose

Antiplatelet Agents

RW is a 63 y/o M PMH DM, HL, dilated NICM s/p LVAD placement (HMII) in 2014. He presents to clinic, where the LVAD coordinator obtains a doppler BP of 130 mmHG. When interrogating the device, what LVAD parameters may be found?

A. Decreased PIB. Increased powerC. Decreased flowD. None of the above

Patient Case

CF-LVAD Thrombosis

Development of clot within the flow path or any/all componentsLeads to pump failure

Uncommon complicationADVANCE trial 6.4% riskHMII up to 6.25% risk

Pump-related risk factors:Inflow cannula malpositionOutflow graft kink/compressionLow flows from low speeds or right-sided

dysfunction

Pump Thrombosis

Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670. http://ejcts.oxfordjournals.org/content/39/3/414/F1.expansion.

Patient-related risk factors:Atrial fibrillationPre-existent LV thrombusProsthetic mechanical valveSepsisSub-therapeutic INRInadequate anti-platelet therapyPro-coagulant states

Hemolysis is a result of shear stress!

Pump Thrombosis

Routine diagnosis of hemolysisPlasma Free Hemoglobin (pfHb) > 40 mg/dLLactate Dehydrogenase (LDH) > 3x ULNHaptoglobin < 10 mg/dLDark red (tea-colored) urine

Power elevations (>10 watts)

ImagingChest x-ray and CT: malpositionEchocardiogram: suboptimal LV unloadingRight-heart catheterization: elevated pressures

Diagnosis of Pump Thrombosis

Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670.

Surgical: VAD exchangeSignificant morbidity

PharmacologyGPIIbIIIa inhibitorsThrombolytics

Intraventricular vs peripheral administration

Modify antithrombotic therapyIncrease aspirin dose (81 to 325 mg daily)Increase goal INRAdd antiplatelet agent (clopidogrel, dipyridamole)

Treatment Options

Management of Pump Thrombosis

Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670.

• Retrospective review; single center, Jan 2006-Nov 2012

• Evidence of hemolysis + high clinical suspicion of VAD thrombosis, n=33 (of 217, 15.2%)

• Mortality: 15/33, 45.5%• Treatment: (7 deaths)– Eptifibatide, n=9– tPA, n=5– Both, n=10

• No treatment, n=9 (5 pump exchanges, 4 deaths)• High mortality rate with and without

pharmacologic treatment

Management of Pump Thrombosis

Lenneman AJ, et al. J Heart Lunt Translant 2013; 32:S186-187.

CW is a 56 y/o F w/ICM s/p LVAD (HMII) who presented to the hospital from LVAD clinic with an increase in LDH to 764 (baseline 295) and persistent elevations in power >10 watts

PMH: CAD, sCHF with BiV ICD, COPD, DM

CW was started on IV heparin upon admission, and resumed her outpatient warfarin (goal INR 2-2.5) and aspirin 325mg qday

Patient Case

Which of the following agents could be added to her anticoagulation regimen?

A. Cilostazol 100mg po bidB. Clopidogrel 75mg po qday C. Dipyridamole 75mg po tidD. B or CE. None of the above

Patient Case Continued

Gastrointestinal Bleeding (GIB)

Most common adverse event after HMII Incidence: 17-31%Frequent and prolonged hospitalizations

Gastrointestinal angiodysplasia (GIAD)Most common cause of GIB: 15-31% of totalArteriovenous malformations (AVMs)Gastric antral vascular ectasia (GAVE)

Retrospective, single-center review of 172 patients19% (32/172) rate of GIB

AVMs: 31% (10/32)

Etiology

Bunte MC, et al. J Am Coll Cardiol 2013;62:2188-96.Draper K, et al. J Heart Lung Transplant

2015;34(1):132-4.

Narrow pulse pressure: ↓ intraluminal pressureVascular dilatation angiodysplasia, AVMsHypoperfusion intestinal mucosa ischemia

Over-expression of angiogenic growth factors

Acquired Von Willebrand DiseaseIncreased shear stress, turbulence, and high

velocitiesVon Willebrand factor cleavage increased

bleeding and decreased platelet-mediated hemostasis

Pathogenesis

GIB: Patient Presentation

Decrease in hemoglobin (Hgb)Obtain coagulation panel (PT/PTT/INR)

Symptoms: symptomatic anemiaFatigue, dizziness, dyspnea on exertionMelena

Hypotension (decreased MAP)Adjust vasoactive medicationsDecrease in PI

Consider volume expansion

Treatment OptionsBlood transfusions to target Hgb

Problematic for patients listed for transplant

Addition of proton pump inhibitor Prophylaxis vs. treatment

Colonoscopy +/- endoscopy: suspected bleeding sites Endoscopic ablation of AVMs

Mechanical clippingCauterizationArgon plasma coagulation (APC)

Surgical resection

Ray R, et al. ASAIO Journal 2014;60:482-483.

Modification of Current Therapy

Cessation of anticoagulationHold warfarin in setting of clinically significant

bleedAssess need for IV heparin when INR < goal

Reduction of anticoagulationDecrease goal INRModify or discontinue antiplatelet therapy

Reduction of CF-LVAD speedIncrease pulse pressure reduce shear stress

Additional TherapiesAnticoagulation protocols

Reductions in response to bleeding

Octreotide Difficult to tolerate: mode of delivery (injection) Adverse effects: nausea and bradycardia

Thalidomide: potent anti-angiogenic compount Inhibition of vascular endothelial growth factor (VEGF) Recurrent GIAD-related bleeding Associated thrombosis REMS program

Lenalidomide: synthetic analog of thalidomide Less non-hematologic adverse effects

Draper K, et al. J Heart Lung Transplant 2015;34(1):132-4.

Preventative Strategies?

Additional studies needed:Blood product usePlatelet aggregometryThromboelastography

Use is currently insufficient to make recommendations

Perioperative bleeding risk stratification

Individualized bleeding scoreCould offer tailored post-operative AC to limit

bleeding

Balancing Act: GIB vs. Thrombus

JH is a 67 y/o M w/ICM s/p DT LVAD (HMII) implant in May 2015, p/w 2 episodes of melena overnight, dizziness, and fatigue. MAP on admission is 55 mmHG. LVAD interrogation shows multiple PI events (decreased).Labs on admission:

Hgb 7.5 mg/dL (baseline 10.0 mg/dL)INR 3.3 (goal INR 2-2.5)

Current medications:Amiodarone 200 mg po qday, aspirin 325 mg po qday,

carvedilol 12.5 mg po bid, furosemide 20 mg po qday, pantoprazole 40 mg po qday, potassium chloride 20 mEq po qday, warfarin 5 mg po qday

Patient Case

JH was transfused 2 units of PRBC and Gastroenterology was consulted with plan for colonoscopy for ? lower GIB. In addition to holding warfarin, what other medication adjustments would you make at this time?

A. Discontinue furosemide 20 mg po qdayB. Discontinue carvedilol 25 mg po bidC. Lower aspirin to 81 mg po qdayD. All of the above

Patient Case Continued

CF-LVAD Infection

EpidemiologyCF-LVADs decreased rate of infection by 50%

Goldstein, et al. INTERMACS registry: 2008-2013 implants; n = 9,372 2nd most common cause of death post 6-month survival Most common:

Sepsis = 23%Pneumonia = 20% Percutaneous site/driveline infection (PSI) = 19%

Causative organisms Staphylococcus species Pseudomonas species

Prominent w/longer VAD supportDifficult to eradicate

Goldstein DJ, et al. J Heart Lung Transplant 2012;31(11):1151-7.

Complications of InfectionAssociation with cerebrovascular events

(CVEs)Persistence of bacteremia > 72 hours

Persistent Pseudomonas aeruginosa blood stream infections 7-fold increase in CVEsMycotic aneurysms

Potential mechanisms of CVEs:Platelet activationAlterations in endothelial functionSystemic inflammationBacterial seeding of cerebral vasculature

Aggarwal A, et al. ASAIO J 2012;94(5):1381-6.

PathophysiologyDisruption or trauma to the barrier between skin

and driveline

Formation of biofilm Increase difficulty to eradicate bacteria Staphylococcus and Pseudomonas

Peri-operatively and post-operatively Average time to occurrence of PSI = ~6 months

PSI locations May remain superficial Spread along driveline path, into pocket or pump Deepen within abdominal wall to form abscess

Trachtenberg B, et al. MDCVJ 2015;11(1):28-32.

Classification of Infection

CVC: central venous catheter

BSI: blood stream infection

SSI: surgical site infection

Trachtenberg B, et al. MDCVJ 2015;11(1):28-32.

PreventionImmobilization of percutaneous lead at exit

sitePrevents disruption of subcutaneous tissue

growthMethods: minimize trauma and tension

Anchoring devicesStabilization belts

Exercise sterile vs. clean technique for exit site care

Patient educationReport increased drainage or erythema

immediatelyGentle and non-traumatic exit site cleaning

Prevention: Perioperative Antibiotics

REMATCH study (HeartMate XVE):Vancomycin 15 mg/kg IV 1 hour pre-op then q12h Levofloxacin 500 mg IV 1 hour pre-op then q24hRifampin 600 mg po 1 hour pre-op then q24hFluconazole 200 mg IV 2 hours pre-op then q24h

Most centers omit rifampin, use β-lactams, or tailor to institutional antibiogramContinue for 48-hours

HeartWare recommendations:Cover S. aureus, S. epidermidis, and Enterococcus

according to institutional antibiogram

Richenbacher WE, et al. Ann Thorac Surg 2003;75:S86-92.

DiagnosisPrompt culture of drainage

3 sets of blood cultures

ImagingChest radiographyEchocardiogram: pacemakers or defibrillator

leadsPresence of valvular endocarditis or device

infectionsUltrasound or CT:

Diagnose collections of fluid around driveline, pump, or pump pocket

Guide aspiration or debridementFeldman D, et al. J Heart Lung Transplant 2013;32(2):157-87.

Diagnosis

Treatment Options Hospitalization criteria:

Signs of systemic infection = fever or leukocytosis

Mild infection: Increase frequency of dressing changes Review dressing change protocols for compliance

Moderate infection: Tailor antibiotic therapy Local debridement Weekly clinic visits

Severe infection: purulent drainage and subcutaneous induration Target antimicrobial therapy with ID consult Imaging tests Surgical interventions: debridement or retunneling of driveline

Trachtenberg B, et al. MDCVJ 2015;11(1):28-32.

Treatment OptionsAdditional tools

Wound vacuum-assisted closure therapy Antimicrobial beads

Chronic suppressive oral antibiotics For recurrent VAD-specific or VAD-related infections 1/3 of patients have recurrence despite antibiotics

Device exchange (severe cases)

Expediting heart transplant listing Studies show no increase in mortality post-transplant

Conclusion

Overview: CF-LVAD Complications

Newer devices improvements in survival

Every VAD patient is different!Importance of understanding VAD-specific

parameters

Balancing act between VAD thrombus and GIB

Preventative measures of infection

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